ABSTRACT It is known that the ?-cell of the islet of Langerhans secretes SST, which inhibits the secretion of the glucoregulatory hormones insulin and glucagon and thus impacts glucose metabolism. In spite of SST being a powerful neurotransmitter and immune-modulator that mediates several physiological functions in different tissues, no other roles have been attributed to the islet ?-cell other than to suppress the secretory capacity of its neighboring ?- and ?-cells. Besides, relatively little is known about the mechanisms that regulate SST secretion in the islet. Our long-term goal is to understand the contribution of the ?-cell to islet biology in health and diabetes. In particular, through this project we will determine what regulates ?-cell activity and novel crucial roles for this cell in the islet. We hypothesize the ?-cell is a signaling hub where endocrine, paracrine and neural signals converge and are integrated to set the level of SST secretion, which is a key element for islet homeostasis. We will text the strength of this hypothesis for both, mouse and human islets. Based on preliminary results, we propose that SST secretion from ?-cells plays a dual role: (1) by providing negative feedback to ?- and ?-cells it prevents runaway secretory responses, thus stabilizes hormonal and other co- secreted molecules output, and (2) it modulates intra-islet immune cell infiltration and activation. Therefore, in this project we will pursue two specific aims: (1) to determine the mechanisms involved in the regulation of ?- cell function and SST secretion, and (2) to determine the role of the ?-cell and SST in islet inflammation and diabetes pathogenesis. We will use a combination of novel in vitro (isolated islets), ex vivo (pancreatic tissue slices), and in vivo (intraocular islet grafts) approaches together with pharmacological tools, optogenetic stimulation, cell ablation, functional imaging and systemic metabolic readouts to study how ?-cells are activated and how they influence surrounding endocrine and immune cells. We expect our studies to further our understanding of the circumstances under which the ?-cell is recruited to influence endocrine and immune cells in the islet. We anticipate potential differences in the regulation and roles of ?-cells and SST for islets in mouse and human. If SST's role as an immunomodulator is validated, it is likely that ?-cell will be reconsidered as a key element in the natural history of diabetes. Therefore important advances in our understanding of the pathogenesis of diabetes could be expected.